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B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406
Open accessAbstract
Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL.
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Ponader, S., Chen, S.-S., Buggy, J. J., Balakrishnan, K., Gandhi, V., Wierda, W. G., Keating, M. J., O'Brien, S., Chiorazzi, N., & Burger, J. A. (2012) · Blood · doi:10.1182/blood-2011-10-386417 · Cited by 640
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Burger, J. A., & Wiestner, A. (2018) · Nature Reviews Cancer · doi:10.1038/nrc.2017.121 · Cited by 431
Self-citationClonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia
Ahn, I. E., Underbayev, C., Albitar, A., Herman, S. E. M., Tian, X., Maric, I., Arthur, D. C., Wake, L., Pittaluga, S., Yuan, C. M., et al. (2017) · Blood · doi:10.1182/blood-2016-06-719294 · Cited by 341
B cell receptor signaling in chronic lymphocytic leukemia
Burger, J. A., & Chiorazzi, N. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.07.002 · Cited by 327
Self-citationFerreira, P. G., Jares, P., Rico, D., Gómez-López, G., Martínez-Trillos, A., Villamor, N., Ecker, S., González-Pérez, A., Knowles, D. G., Monlong, J., et al. (2014) · Genome Research · doi:10.1101/gr.152132.112 · Cited by 214
Inflammation and survival pathways: Chronic lymphocytic leukemia as a model system
Chen, L. S., Balakrishnan, K., & Gandhi, V. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.07.039 · Cited by 55
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Metadata
- Authors
- Quiroga, M. P., Balakrishnan, K., Kurtova, A. V., Sivina, M., Keating, M. J., Wierda, W. G., Gandhi, V., & Burger, J. A.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2009-07-30
- Volume
- 114
- Issue
- 5
- Pages
- 1029-1037
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1972593274
- Cited by
- 237
- References
- 1
- FWCI
- 11.43
- Type
- journal article
- Language
- en
- Open access
- green
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